In response to stressors, the hypothalamic-pituitary-adrenal (HPA) axis is activated, resulting in the release of glucocorticoids from adrenal cortex. Functional and circuitry disturbances of dopaminergic neurons underlie many psychiatric disorders. Nevertheless, mechanistic links of this endocrine system to dopaminergic neurons in the disease contexts remain elusive. This applicant has previously reported that four different Disc1 genetically-engineered mice (DISC1 mice) manifest various behavioral deficits relevant to psychiatric disorders and show dopaminergic disturbance, suggesting that dopaminergic disturbance may be a central and common deficit in these models. Psychiatric conditions are usually elicited not merely by genetic factor(s), however, but by a combination of gene-environmental factors. Thus, we hypothesized that DISC1 mice might be useful models with which to examine how stressors modify the dopamine-associated pathologies, and further hypothesized that the HPA axis might participate in the mechanism. To address these questions, we have used a transgenic model expressing a dominant-negative mutant DISC1 under the expression control of the prion protein promoter (DISC1-DN-Tg-PrP) in combination with isolation stress during adolescence. We will examine whether blocking overactivation of the HPA axis normalizes dopaminergic disturbance and behavioral deficits in this model. We hypothesize that cell-autonomous epigenetic mechanisms in response to glucocorticoids may underlie, at least in part, the distinct regulation of mesocortical and mesolimbic dopaminergic projections in the mice. To address this question, we will use several technologies that allow us to examine molecular assessment of circuitry in a projection-dependent manner. Using mice with glucocorticoid receptor (GR) deletion based on dopamine transporter expression, we will also address the role of GR in disturbance of dopaminergic neurons in DISC1-DN-Tg-PrP mice with isolation. Here we plan to examine overall interactions of endocrine-epigenetic-neuron systems in the pathophysiology of psychiatric disorders that occur under synergistic influence of genetic-environmental factors. This training and research proposal will enable this applicant to develop into an independent investigator in psychiatric research. The mechanism(s) of endocrine-epigenetic-neuron systems can be extended towards translational approaches in the near future. PUBLIC HEALTH RELEVANCE: Although dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis by response to stressors and disturbance of dopaminergic neurons has been suggested in patients with psychiatric disorders, the mechanistic link of the endocrine system to dopaminergic neurons in disease contexts remain unclear. In this study, we will characterize the key role of glucocorticoids in dopaminergic dysfunction in transgenic mice expressing mutant DISC1, a strong risk factor for psychiatric disorders, under environmental stresses. The study will contribute to the further understanding of endocrine-epigenetic-neuron communication, as well as identification of novel therapeutic target(s) that enables early intervention treatment for psychiatric disorders.